Beyond BCMA: newer immune targets in myeloma

Abstract

The identification and targeting of B-cell maturation antigen (BCMA) through immunotherapeutic strategies such as antibody-drug conjugates, chimeric antigen receptor T cells, and T-cell engagers have revolutionized the care of patients with multiple myeloma (MM). These treatment modalities have improved the survival outcomes of patients with relapsed and/or refractory MM compared with previously established strategies and are moving into earlier lines of therapy. Despite their efficacy, the majority of patients eventually relapse, necessitating additional therapeutic targets for salvage. G-protein-coupled receptor class 5 member D, Fc receptor-homolog 5, and SLAMF7 are some examples of novel targets in development. This expanding armamentarium of immunotherapeutic agents will be crucial to address the unmet need for relapses after BCMA-targeting therapies, particularly antigen-negative relapses. The utilization of sequential T-cell redirective therapies including agents targeting different tumor-associated antigens and combination therapies appears feasible, paving the way for effective chemotherapy-free regimes. Deliberate consideration of treatment timing, preserving T-cell health, overcoming antigenic loss, and comprehension of the complex tumor microenvironment would be key to maximizing therapeutic benefits and minimizing adverse effects. This review summarizes novel targets in development for myeloma beyond BCMA, presenting pivotal safety and efficacy data derived from clinical trials when available and the considerations vital for navigating this expanding landscape of immunotherapeutic options.

Figure 1.

Summary of immunotherapies with novel targets and therapeutics. Highlighted in red are FDA-approved therapies. Figure created with BioRender.com.

Figure 2.

Prospective developments in the treatment paradigm for R/R MM. (A) The current challenges and future directions in MM diagnostics, MRD monitoring, and treatment approaches. (B) We depict a theoretical roadmap outlining a patient example of treatment options and considerations in the treatment of R/R MM. Figure created with BioRender.com. MRD, minimal residual disease.